The goals of this thematic area are to analyze the molecular mechanisms of replication and pathogenicity associated with selected NIAID category A viruses. Seven subprojects in this theme use multi-disciplinary approaches each focused on the PI's area of expertise. Several platforms are used to address issues from basic biology to the development of novel antiviral agents. Erich Mackow (subproject 1) will develop "reverse genetics" systems for hantaviruses, techniques critical for the study of hantavirus molecular biology and virulence, as well as for the rational development of attenuated vaccines and the characterization of potential anti-hantavirus agents. Subprojects 2, 3 and 4 will investigate the interactions between category A RNA viruses and the type I IFN response of the host, a first line of host defense against viral infection. Drs. Basler and Garcla-Sastre (subprojects 2 and 3) will focus on identification, characterization and inhibition of viral factors that counteract this important host defense system. Drs. Levy and Marie (subproject 4), will study the signaling determinants of mammalian innate immune responses in order to characterize the molecular mechanisms underlying host defense. These studies will also explore antiviral strategies aimed towards inhibiting viral-encoded interferon antagonists. Since age is an important factor influencing morbidity and mortality associated with viral infection, Drs. Hornig and Lipkin (subproject 5) will assess the age-related endocrine and immune factors in viral encephalitis using a mouse model of West Nile virus. Understanding the age-related factors influencing virus pathogenicity will be critical for the rational design of antiviral therapies in young infants and the elderly. Subprojects 6 and 7 explore novel strategies aimed towards the development of new classes of antivirals. Drs. MacDonald and Rice will utilize a general approach to identify new potential antiviral targets for dengue (NIAID Category A Priority Pathogen), West Nile (Category B) and yellow fever (Category C) viruses. They will seek to identify functionally important protein:protein interactions and explore these as possible targets for the development of new and improved antivirals. Dr. David Ron (subproject 7), will explore whether the interactions of enveloped viruses with the host cell's ER machinery can be exploited to develop novel antiviral therapies against a broad class of viruses. He will target the signaling pathways that constitute an Unfolded Protein Response (UPR) that regulates the ER machinery. We expect this collaborative effort to lead to the development of a more complete picture on how highly pathogenic viruses induce disease, as well as to the discovery of novel therapeutic targets and molecules.